Agent for treating nocturnal pollakiuria

ABSTRACT

[Problem] To provide a novel therapeutic agent for nocturnal pollakiuria.[Solution] A therapeutic agent for nocturnal pollakiuria which contains, as an active ingredient, (6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide.

TECHNICAL FIELD

The present invention relates to an agent for treating nocturnalpollakiuria.

BACKGROUND ART

Nocturnal pollakiuria is a complaint that one has to wake up one or moretimes for urinating at night, and is one of the symptoms (urinaryurgency, pollakiuria, nocturnal pollakiuria, and urge urinaryincontinence) resulting from overactive bladder (OAB). Nocturnalpollakiuria causes nocturnal awakening and is closely associated withsleep disorders, thereby reducing QOL remarkably (Non Patent Literature1).

Desmopressin, which is an agonist of vasopressin V2 receptor, has beenknown so far as a therapeutic drug for nocturnal pollakiuria: however,desmopressin has a risk of serious adverse reactions such as waterintoxication (hyponatremia) and can be administered only to a restrictedgroup of patients (Non Patent Literature 2).

Furthermore, mirabegron, which is an agonist of β3 adrenergic receptor,can be administered only to a restricted group of patients. For example,administration of mirabegron to patients of reproductive age needs to beavoided (Non Patent Literature 3). There has been no report onmirabegron indicating a significant difference in therapeutic effect onnocturnal pollakiuria in Japanese subjects as compared with a placebo(Non Patent Literatures 4 to 9).

Vibegron (a compound represented by general formula (1) or expressed as(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide)is known as a compound that is an agonist of β3 adrenergic receptorsimilarly to mirabegron (Patent Literature 1).

CITATION LIST Patent Literature

-   Patent Literature 1: International Publication No. WO 2009124167

Non Patent Literature

-   Non Patent Literature 1: Nihon Hainyou Kinou Gakkai Yakanhinnyou    Sinryou Guideline Sakusei Iinkai (in Japanese) (Preparation    Committee on Practice Guideline for Nocturnal Pollakiuria of The    Japanese Continence Society) (2009), Yakanhinnyou Sinryou Guideline    Dai 1 Pan (in Japanese) (Practice Guideline for Nocturnal    Pollakiuria, the first edition).-   Non Patent Literature 2: Neurourol Urodyn 2004; 23: 302-305, Package    inserts of Minirinmelt OD tablet 60 μg, Minirinmelt OD tablet 120    μg, and Minirinmelt OD tablet 240 μg, revised in March 2017 (the    fourth edition).-   Non Patent Literature 3: Package inserts of Betanis (R) 25 mg and    Betanis (R) tablet 50 mg, revised in March 2016 (the ninth edition).-   Non Patent Literature 4: Interview forms of Betanis (R) tablet 25 mg    and Betanis tablet (R) 50 mg, revised in 2016.-   Non Patent Literature 5: Neurourology and Urodynamics (2015), 34    (7), 685-692.-   Non Patent Literature 6: BJU International (2014), 113 (6), 951-960.-   Non Patent Literature 7: International Journal of Urology (2014), 21    (10), 960-967.-   Non Patent Literature 8: Neurourology and Urodynamics (2013), 32    (8), 1116-1122.-   Non Patent Literature 9: Journal of Urology (New York, N.Y., United    States) (2013), 189 (4), 1388-1395.

SUMMARY OF INVENTION Technical Problem

It is an object of the present invention to provide a novel agent fortreating nocturnal pollakiuria.

Solution to Problem

The present inventors have conducted extensive studies of a moreeffective and safe agent for treating nocturnal pollakiuria.Consequently, the present inventors have found that a compoundrepresented by general formula (1), namely,(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis highly effective as the agent for treating nocturnal pollakiuria andcompleted the present invention.

The present invention includes the following embodiments.

[1] An agent for treating nocturnal pollakiuria comprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient.[2] The agent according to [1], wherein the agent for treating nocturnalpollakiuria is administered to a subject belonging to a group ofpatients whose average value of the frequency of urination at night is1.0 or more and 1.8 or less.[3] The agent according to [1] or [2], wherein the agent is administeredorally once daily at a daily dosage of 50 mg or more and 100 mg or lessof the active ingredient.[4] An agent for nocturnal pollakiuria comprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient, wherein the agent is administered to an Asian.[5] An agent for treating nocturnal pollakiuria comprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient, wherein the agent is administered to aJapanese.[6] An agent for treating sleep disorder associated with nocturnalpollakiuria comprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient.[7] The agent according to any one of [1] to [6], wherein the nocturnalpollakiuria is nocturnal pollakiuria without nocturnal polyuria.[8] A method for treating nocturnal pollakiuria, comprisingadministering to a subject in need thereof(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidein an effective amount to treat nocturnal pollakiuria.[9] The method according to [8], wherein(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered to a subject belonging to a group of patients whoseaverage value of the frequency of urination at night is 1.0 or more and1.8 or less.[10] The method according to [8] or [9], wherein(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered orally once daily at a daily dosage of 50 mg or more and100 mg or less.[11] Use of(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidein the manufacture of a medicament for treating nocturnal pollakiuria.[12] The use according to [11], wherein(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered to a subject belonging to a group of patients whoseaverage value of the frequency of urination at night is 1.0 or more and1.8 or less.[13] The use according to [11] or [12], wherein(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered orally once daily at a daily dosage of 50 mg or more and100 mg or less.[14] A compound(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidefor treating nocturnal pollakiuria.[15] The compound for treating nocturnal pollakiuria according to [14],wherein the compound is administered to a subject belonging to a groupof patients whose average value of the frequency of urination at nightis 1.0 or more and 1.8 or less.[16] The compound for treating nocturnal pollakiuria according to [14]or [15], wherein the compound is administered orally once daily at adaily dosage of 50 mg or more and 100 mg or less.

Advantageous Effects of Invention

The agent of the present invention has an excellent effect of reducingthe frequency of urination at night, and thus, can be usedadvantageously as the agent for treating nocturnal pollakiuria.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the least squares mean (ΔLSmean) of the amountof change from baseline in the frequency of urination at night after 12weeks of administration.

FIG. 2 is a graph showing the least squares mean (ΔLSmean) of the amountof change from baseline in the single voided volume at night after 12weeks of administration in a group of patients whose frequency ofurination at night is one or more times per day at baseline.

FIG. 3 is a graph showing the least squares mean (ΔLSmean) of the amountof change from baseline in the time to first awakening (HUS: hours ofundisturbed sleep) after 12 weeks of administration in a group ofpatients whose frequency of urination at night is one or more times perday at baseline.

FIG. 4 is a graph showing the least squares mean (ΔLSmean) of the amountof change from baseline in the first voided volume at night after 12weeks of administration in a group of patients whose frequency ofurination at night is one or more times per day at baseline.

DESCRIPTION OF EMBODIMENTS

Hereinafter, an embodiment of the present invention will be described indetail, but the present invention is not limited to this embodiment.

As used herein, “nocturnal pollakiuria” refers to a condition in whichone has to wake up one or more times for urinating at night. “At night”refers to the period of time between when one goes to bed to sleep andwhen one wakes up and gets out of bed.

Parameters for expressing the level of nocturnal pollakiuria include“frequency of nocturnal pollakiuria” and “frequency of urination atnight.” The former represents the frequency of urination that wasrecorded during sleep at night, provided that one is sleeping before andafter urination. Therefore, the number of times when one was unable tosleep after getting into bed and went to the toilet is not counted inthe “frequency of nocturnal pollakiuria.” On the other hand, the latterrepresents the frequency of urination between the timepoint when onewent to bed for sleeping and the timepoint when one got up (got out ofbed) for rising. Therefore, urination that was done after going to bedand before falling asleep and urination that was done after awaking andurinating early morning and before falling asleep again are counted inthe frequency of urination at night. Herein, the frequency of urinationat night is used to evaluate the level of nocturnal pollakiuria.

As used herein, “treatment” refers to alleviating or reducing at leastone of the diseases or conditions of a subject.

The agent for treating nocturnal pollakiuria of the present inventionrelaxes the bladder, thereby enhancing urine storage function thereof.Therefore, the agent is preferably used for “nocturnal pollakiuriaassociated with a reduced capacity of the bladder”, and is morepreferably used for “nocturnal pollakiuria associated with overactivebladder.”

The agent for treating nocturnal pollakiuria of the present invention ispreferably administered to a human. In this specification, examples ofthe human include an Asian, a Caucasian, a colored person, an AfricanAmerican, and a Hispanic. The agent for treating nocturnal pollakiuriaof the present invention is preferably administered to an Asian, andmore preferably administered to a Japanese (A significant differencecompared with a placebo was seen when the agent for treating nocturnalpollakiuria of the present invention was administered to a Japanese).

An “Asian” as used herein is synonymous with the term generally used inclinical studies and examples thereof include a Taiwanese, a Korean, aChinese, and a Japanese.

A “Japanese” as used herein is synonymous with the term generally usedin clinical studies, and has a narrower meaning compared with agenerally used definition of a Japanese, which is based on nationality.More specifically, the “Japanese” as used herein refers to a personwhose parents and grandparents are not a foreigner. Therefore, a personwhose at least one of the father and the mother is a foreigner and aperson whose at least one of the grandfathers and the grandmothers is aforeigner are excluded from the definition of “Japanese” used herein.

An “average value of the frequency of urination at night” as used hereinrefers to an average value of the frequency of urination between whenone goes to bed to sleep and when one wakes up and gets out of bed. Thisaverage value is zero or more and less than one in a population ofhealthy subjects and is 1.0 or more in a population of patients withnocturnal pollakiuria. A group of patients with a higher numerical valueis a group of patients with severer nocturnal pollakiuria. The agent fortreating nocturnal pollakiuria of the present invention is moreeffective for a group of patients with mild to severe nocturnalpollakiuria, and preferably is administered to a subject belonging to agroup of patients whose average value of the frequency of urination atnight is 1.0 or more. For example, the agent is administered to asubject belonging to a group of patients whose average value of interestis more preferably 1.0 or more and 1.8 or less, even more preferably 1.2or more and 1.8 or less, and particularly preferably 1.3 or more and 1.7or less. In this context, the “average value of the frequency ofurination at night” may be referred to as “average frequency ofurination at night.”

A “single voided volume at night” as used herein refers to a voidedvolume per urination at night.

“Time to first awakening” as used herein may be referred to as HUS(hours of undisturbed sleep) and refers to time from falling asleep tofirst awakening to urinate.

A “first voided volume at night” as used herein refers to a voidedvolume of the first urination at night.

A pharmaceutical composition comprising a pharmaceutically acceptableadditive may be used as an agent for treating nocturnal pollakiuriacomprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient. Examples of the pharmaceutically acceptableadditive include an excipient, a lubricant, a binder, a disintegrant, astabilizer, a flavoring agent, and a diluent. These additives are notparticularly limited as long as they can be used for manufacturing apharmaceutical preparation, and for example, those listed in “JapanesePharmaceutical Excipients Directory (International PharmaceuticalExcipients Council Japan, Yakuji Nippo, Limited (2016)) can be used asappropriate.

“Comprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient” means that any substance can be used as long asthe substance comprises(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideas an active ingredient. Thus, a pharmaceutically acceptable salt or acocrystal thereof may be administered when administered to a subject.

The pharmaceutically acceptable salt of(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidemeans a salt with a pharmaceutically acceptable nontoxic acid (forexample, an organic acid or an inorganic acid). Examples of the saltwith a pharmaceutically acceptable nontoxic acid include an acidaddition salt with a mineral acid such as hydrochloric acid, hydrobromicacid, sulfuric acid, and nitric acid and an acid addition salt with anorganic acid such as formic acid, acetic acid, maleic acid, fumaricacid, succinic acid, lactic acid, malic acid, tartaric acid, citricacid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid,stearic acid, and palmitic acid.

The pharmaceutically acceptable cocrystal of(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidemeans a cocrystal with a generally used cocrystal former. Examples ofthe generally used cocrystal former include those described in WO2004078163.

Furthermore,(6S)—N-[4-({((2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideor a pharmaceutically acceptable salt thereof may exist as a hydrate.

Furthermore,(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideor a pharmaceutically acceptable salt thereof may exist in a pluralityof crystal forms or non-crystal (amorphous) forms, and any of thecrystal forms or non-crystal forms may be administered.

The agent of this embodiment can be administered to a subject such as ahuman by applying a form and an administration route that areconventionally well known in the pharmaceutical field. For example, theagent can be administered orally or parenterally as a formulation suchas a powder, a tablet, a capsule, a fine granule, a granule, a syrup, aninjection, an ophthalmic solution, an aqueous nasal drop, an aqueous eardrop, and an inhalation solution. Specifically, the agent of thisembodiment can be produced for example in the dosage form as describedabove by mixing the active ingredient with a carrier, an excipient, abinder, a diluent, and the like that are physiologically acceptable.

In order that the agent of this embodiment can exert a medicinal effectand reduce adverse reactions, a daily dosage of(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis preferably 10 mg or more and 250 mg or less, for example in the caseof oral administration. The daily dosage is more preferably 30 mg ormore and 160 mg or less, even more preferably 40 mg or more and 150 mgor less, and still more preferably 50 mg or more and 100 mg or less.More specific examples of the daily dosage include 50 mg, 62.5 mg, 75mg, 87.5 mg, and 100 mg, among which 50 mg is more preferable. The dailydosage may be increased up to 100 mg depending on the symptoms. Althoughthe daily dosage may be administered as a single dose or as two to threedivided doses, a once daily dosing is preferable.

When the pharmaceutically acceptable salt, cocrystal, or hydrate of(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis used, the above daily dosage is an amount in terms of free formthereof.

The “free form” refers to(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidenot in any form of a salt, a cocrystal, or a hydrate, and is a compoundwhose molecular formula is C₂₆H₂₈N₄O₃ and molecular weight is 444.53.

This embodiment can provide an agent for treating nocturnal pollakiuriathat is excellent in efficacy and safety.

Furthermore, one aspect of the present invention relates to a method fortreating nocturnal pollakiuria, comprising administering to a subject inneed thereof(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidein an effective amount to treat nocturnal pollakiuria.

Furthermore, one embodiment of the present invention relates to a use of(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidein the manufacture of a medicament for treating nocturnal pollakiuria.

Furthermore, one aspect of the present invention relates to(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidefor treating nocturnal pollakiuria.

Again, in these aspects, any substance can be used as long as(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis used as the active ingredient. Thus, a pharmaceutically acceptablesalt or a cocrystal thereof may be administered when administered to asubject.

Examples

The present invention will be described in more detail with reference tothe following Examples, but these Examples are not intended to limit thescope of the present invention.

Vibegron (compound represented by general formula (1) or(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide)was produced according to the method disclosed in WO 2009124167. Aformulation to be administered orally to patients was produced by usingan additive and a production method that were generally used.

The efficacy of vibegron on nocturnal pollakiuria in OAB patients wasevaluated in a twelve-week randomized, double-blind, placebo-controlled,parallel-group study.

Japanese OAB patients received either vibegron (50 mg/day or 100 mg/day)or a placebo for 12 weeks. Both 50 mg/day of vibegron and 100 mg/day ofvibegron were orally administered in the form of a tablet once dailyafter breakfast. Table 1 shows the demographic characteristics ofsubjects. There was no difference among the dose groups in terms ofsubject background such as gender, age, and BMI.

The therapeutic effect of vibegron on nocturnal pollakiuria in OABpatients was evaluated based on an average frequency of urination atnight, which was determined by using a urination diary to investigatethe frequency of urination for three days prior to visits. In thiscontext, nighttime is defined as the period of time between when onegoes to bed to sleep and when one wakes up and gets out of bed. Theevaluation results are shown in Table 2 and FIG. 1. Constrainedlongitudinal data analysis model (cLDA) was used for statisticalanalysis to estimate the least squares mean and the two-sided 95%confidence interval of each group. Furthermore, the cLDA method was usedto estimate the least squares mean difference at evaluation timesbetween the 50 mg or 100 mg vibegron groups and the placebo group andthe two-sided 956 confidence intervals thereof, thereby testing theleast squares mean difference compared with placebo.

Numerical values in Table 2 represent the average of the frequency ofurination at night at baseline (before drug administration), the leastsquares mean of the amount of change from baseline in the averagefrequency of urination at night after 12 weeks of administration, theleast squares mean of difference in the amount of change between thevibegron groups and the placebo group, and p-values. In this regard,when the amount of change is less than 0, the smaller value represents agreater therapeutic effect. Furthermore, a p-value less than 0.05indicates that there is a significant difference between the vibegrongroups and the placebo group. “Patients whose frequency of urination atnight is not zero at baseline” are represented as a main subjectpopulation, and other “patients whose frequency of urination at night isone or more times at baseline” and “patients whose frequency ofurination at night is two or more times at baseline” are represented aspopulations who have more prominent symptoms of nocturnal pollakiuria.FIG. 1 is a graph in which the numerical values represent the leastsquares mean (ΔLSmean) of the amount of change from baseline in thefrequency of urination at night after 12 weeks of administration.

TABLE 1 Demographic Characteristics Vibegron 50 mg Vibegron 100 mgPlacebo Number of Number of Number of Item subjects: 370 subjects: 368subjects: 369 Gender Number of female subjects (%) 334 (90.3) 330 (89.7)333 (90.2) Number of male subjects (%) 36 (9.7) 38 (10.3) 36 (9.8) AgeMean value ± standard deviation 58.0 ± 11.8 58.7 ± 11.1 58.9 ± 11.8 BMI(kg/cm²) Mean value ± standard deviation 23.00 ± 4.00  23.15 ± 4.16 23.22 ± 3.96  OAB Disease duration Mean value ± standard deviation 58.3± 63.2 69.8 ± 75.2 58.2 ± 59.3 (months)

TABLE 2 The Amount of Change from Baseline in the Frequency of Urinationat Night after 12 Weeks of Administration Difference in amount of changeAmount of change (vibegron group − placebo group) Number Average Leastsquares mean Least squares of at (95% confidence mean (95% Subjectpopulation Dose group subjects baseline interval) confidence interval)p-value Patients whose frequency of Vibegron 50 mg 312 1.37 −0.58(−0.65, −0.51) −0.11 (−0.21, −0.02) 0.0158 urination at night is notzero Vibegron 100 mg 304 1.36 −0.62 (−0.70, −0.55) −0.16 (−0.25, −0.06)0.0012 at baseline Placebo 313 1.41 −0.47 (−0.54, −0.40) Patients whosefrequency of Vibegron 50 mg 227 1.69 −0.74 (−0.82, −0.65) −0.16 (−0.28,−0.04) 0.0073 urination at night is one or Vibegron 100 mg 218 1.69−0.78 (−0.87, −0.70) −0.21 (−0.33, −0.09) 0.0007 more times at baselinePlacebo 224 1.75 −0.58 (−0.66, −0.49) Patients whose frequency ofVibegron 50 mg 80 2.45 −1.00 (−1.17, −0.83) −0.15 (−0.38, 0.08)  0.2051urination at night is two or Vibegron 100 mg 76 2.51 −1.16 (−1.34.−0.99) −0.31 (−0.55, −0.08) 0.0093 more times at baseline Placebo 802.60 −0.85 (−1.02, −0.68)

As can be seen from Table 2 and FIG. 1, the 50 mg vibegron group and the100 mg vibegron group exhibited a significant therapeutic effect onnocturnal pollakiuria in the patients who urinated at night (whosefrequency of urination at night was not zero at baseline) compared withthe placebo group. Furthermore, the vibegron groups also exhibited anexcellent therapeutic effect on nocturnal pollakiuria in the populationshaving more prominent symptoms of nocturnal pollakiuria whose frequencyof urination at night was one or more times or two or more times (one ormore at baseline). It was found from the results described above thatvibegron served as a highly effective therapeutic agent on nocturnalpollakiuria.

As is shown in FIG. 2, the single voided volume at night of the group ofpatients whose frequency of urination at night was one or more times perday (one or more at baseline) increased significantly in the 50 mgvibegron group (+47.85 mL) and the 100 mg vibegron group (+58.14 mL)compared with the placebo group (+19.42 mL). This result suggests thatincrease in the single voided volume at night possibly contributed toreduction in the frequency of urination at night.

Furthermore, as is shown in FIG. 3, the time to first awakening of thegroup of patients whose frequency of urination at night was one or moretimes per day (one or more at baseline) was extended in the 50 mgvibegron group (81.79 minutes) and more significantly in the 100 mgvibegron group (90.95 minutes) compared with the placebo group (65.08minutes). Furthermore, as is shown in FIG. 4, the first voided volume atnight of the group of patients whose frequency of urination at night wasone or more times per day (one or more at baseline) was increasedsignificantly in the 50 mg vibegron group (48.71 mL) and the 100 mgvibegron group (71.42 mL) compared with the placebo group (24.80 mL).

TABLE 3 Vibegron 50 mg Vibegron 100 mg Parameters n ρ^(†) p-value Nρ^(†) p-value (1) Time to first 224 −0.670 <0.001 208 −0.622 <0.001awakening vs. frequency of urination at night (2) Time to first 224  0.419 <0.001 208   0.423 <0.001 awakening vs. first voided volume atnight ^(†)Spearman's rank correlation coefficient

It is found from Table 3 that there is positive correlation between thetime to first awakening and the first voided volume at night (50 mgvibegron group: ρ=0.419, 100 mg vibegron group: ρ=0.423). It is alsofound that there is negative correlation between the time to firstawakening and the frequency of urination at night (50 mg vibegron group:ρ=−0.670, 100 mg vibegron group: ρ=−0.622). The time to first awakeninghas been reported to be important for ensuring quality of sleep (Eur.Urol. Suppl. 2006; 5: 3-11), and moreover, it has been suggested thatthe first three hours of sleep contribute to quality of sleep (Sleep1991; 14: 294-306). As described above, nocturnal pollakiuria greatlyaffects sleep and reduces QOL of patients. Considering this, vibegron isalso promising as an agent for treating sleep disorders resulting fromurination at night, since vibegron increases time to first awakening byreducing the frequency of urination at night as well as increasing thefirst voided volume at night.

The groups of patients whose frequency of urination at night was one ormore times per day at baseline were compared based on the presence orabsence of nocturnal polyuria.

In the group of patients with nocturnal pollakiuria without nocturnalpolyuria, the frequency of urination at night was significantly reducedin the 50 mg vibegron group and the 100 mg vibegron group compared withthe placebo group; and the single voided volume at night wassignificantly increased in the 50 mg vibegron group and the 100 mgvibegron group compared with the placebo group. On the other hand, in agroup of patients with nocturnal pollakiuria with nocturnal polyuria,the frequency of urination at night was reduced in the 50 mg vibegrongroup and the 100 mg vibegron group compared with the placebo group butthe difference was not significant. However, the single voided volume atnight was significantly increased in the 50 mg vibegron group and the100 mg vibegron group compared with the placebo group.

Desmopressin, which is an agonist of vasopressin V2 receptor, has beenknown so far as a drug for treating nocturnal pollakiuria: however,desmopressin has a risk of serious adverse reactions such as waterintoxication (hyponatremia) and can be administered only to a restrictedgroup of patients (Neurourol Urodyn 2004; 23: 302-305, Package insertsof Minirinmelt OD tablet 60 μg, Minirinmelt OD tablet 120 μg, andMinirinmelt OD tablet 240 μg, revised in March 2017 (the fourthedition)). In contrast, vibegron can be administered to more patientswith nocturnal pollakiuria, since it is a highly safe compound, andthus, vibegron is an excellent agent for treating nocturnal pollakiuria.

INDUSTRIAL APPLICABILITY

This embodiment can provide a novel agent for treating nocturnalpollakiuria comprising(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideand is industrially useful.

1-3. (canceled)
 4. A method for treating nocturnal pollakiuria,comprising administering to a subject in need thereof(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamidein an effective amount to treat nocturnal pollakiuria.
 5. The methodaccording to claim 4, wherein the(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered to a subject belonging to a group of patients whoseaverage value of frequency of urination at night is 1.0 or more and 1.8or less.
 6. The method according to claim 4, wherein the(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered orally once daily at a daily dosage of 50 mg or more and100 mg or less.
 7. The method according to claim 6, wherein the(6S)—N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamideis administered to a subject belonging to a group of patients whoseaverage value of frequency of urination at night is 1.0 or more and 1.8or less.